Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance

Biochemistry
Mina HenesTroy W Whitfield

Abstract

Protease inhibitors have the highest potency among antiviral therapies against HIV-1 infections, yet the virus can evolve resistance. Darunavir (DRV), currently the most potent Food and Drug Administration-approved protease inhibitor, retains potency against single-site mutations. However, complex combinations of mutations can confer resistance to DRV. While the interdependence between mutations within HIV-1 protease is key for inhibitor potency, the molecular mechanisms that underlie this control remain largely unknown. In this study, we investigated the interdependence between the L89V and L90M mutations and their effects on DRV binding. These two mutations have been reported to be positively correlated with one another in HIV-1 patient-derived protease isolates, with the presence of one mutation making the probability of the occurrence of the second mutation more likely. The focus of our investigation is a patient-derived isolate, with 24 mutations that we call "KY"; this variant includes the L89V and L90M mutations. Three additional KY variants with back-mutations, KY(V89L), KY(M90L), and the KY(V89L/M90L) double mutation, were used to experimentally assess the individual and combined effects of these mutations on DRV inhib...Continue Reading

References

Nov 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·W E HarteD L Beveridge
Jan 18, 1994·Proceedings of the National Academy of Sciences of the United States of America·P H Patel, B D Preston
Jun 1, 1993·Journal of Protein Chemistry·J O HuiR L Heinrikson
Jan 16, 2002·Protein Science : a Publication of the Protein Society·Nancy M KingCelia A Schiffer
Jul 5, 2002·Journal of Molecular Biology·Matthew P JacobsonBarry Honig
Mar 30, 2004·Proteins·Matthew P JacobsonRichard A Friesner
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jun 15, 2006·Journal of the American Chemical Society·Hirotaka OdeTyuji Hoshino
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson
Mar 11, 2008·AIDS Research and Human Retroviruses·Sandra de MeyerMarie-Pierre de Béthune
Mar 22, 2008·The Journal of Antimicrobial Chemotherapy·Luis M F GonzalezMarcelo A Soares
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Nigel W MoriartyPaul D Adams
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Feb 18, 2010·Journal of Chemical Theory and Computation·Christopher L McClendonMatthew P Jacobson
Jun 15, 2010·Journal of Chemical Theory and Computation·Yufeng Cai, Celia A Schiffer
Jul 28, 2010·Journal of Virology·Michael E AbramStephen H Hughes
Jul 28, 2010·Antimicrobial Agents and Chemotherapy·Soo-Yon RheeRobert W Shafer
Mar 29, 2011·Nature Genetics·Trevor HinkleySebastian Bonhoeffer
Dec 1, 2009·Viruses·Irene T Weber, Johnson Agniswamy
Apr 5, 2012·Cold Spring Harbor Perspectives in Medicine·Eric J Arts, Daria J Hazuda
Aug 29, 2012·PLoS Computational Biology·Elisabeth Humphris-NarayananTanja Kortemme
Sep 13, 2012·PLoS Computational Biology·Omar HaqRonald M Levy
Oct 23, 2012·The Journal of Antimicrobial Chemotherapy·Farbod BabrzadehRobert W Shafer

❮ Previous
Next ❯

Citations

Feb 24, 2021·ACS Chemical Biology·Gordon J LockbaumCelia A Schiffer
Jan 8, 2021·Chemical Reviews·Ashley N MatthewCelia A Schiffer
Mar 31, 2021·Journal of Chemical Theory and Computation·Florian LeidnerCelia A Schiffer

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.